Hierarchy of Protein Structure

We now begin to build our way up to the three dimensional (3-D) structure of a protein. The 3-D structure of any protein is complicated, so to help us understand we have developed a convenient way to organise, model, and 'picture' this structure.

In particular, Linderstrom-Lang (1952) first proposed that there was a hierarchy of protein structure with four levels: primary, secondary, tertiary, and quaternary. You are probably familiar with this hierarchy as this structural classification is the most convenient starting point for teaching basic protein structure. To revise:

• Primary structure is the basic level of the hierarchy and is the particular linear sequence of amino acids that comprises one polypeptide chain.

• Secondary structure is the next 'level up' from the primary structure and is the regular folding of regions within one polypeptide chain into particular structural patterns. Secondary structures are usually held together by hydrogen bonds between the carbonyl oxygen and the the amide hydrogen of the peptide bond.

• Tertiary structure is the next 'level up' from the secondary structure and is the particular three-dimensional arrangement of all the amino acids in one polypeptide chain. This structure is usually the native, and active, conformation and is held together by multiple noncovalent interactions.

• Quaternary structure is the next 'level up' from the tertiary structure and is the particular spatial arrangement, and interactions, between two or more polypeptide chains.

The implications of this hierarchy are that:

• each level of the hierarchy is 'held together' by characteristic interactions and forces
• higher levels of structure in the hierarchy are composed of the structural entities (also called elements) of the lower levels 

However, subsequent work has revealed that this four-level hierarchy of protein structure is a bit too simple and the three dimensional structure of proteins can now be conveniently described by a six level structural hierarchy, shown in (Figure 1), which includes:

• primary structure
• secondary structure
• supersecondary structure
• domain structure
• tertiary structure
• quaternary structure.

Figure 1. Protein Hierarchy

The definitions of primary, secondary, tertiary, and quaternary structure are as above and the definitions of the other levels of structure are:

Supersecondary structure is the next level up from secondary structure and involves the association of secondary structures. Also known as structural motifs¹.

Domains are larger associations of two or more secondary structures, two or more supersecondary elements, or mixtures of two or more secondary and supersecondary structures. They can also be known as 'folds', and 'modules'. As we will see later in Protein Tertiary Structure domains are independently folding units of tertiary structure and contain between 35 and 200 amino acids. Note that some other authors may present slightly different definitions of the terms above and we will look at some definitions later in Protein Tertiary Structure.

Motif. Please note that the term 'motif' is often used in other contexts. For example, a motif can be either a structural or a sequence motif:

• A structural motif is the arrangement of atoms in 3-D space to produce a particular structural pattern eg. alpha helix, beta sheet.
• A sequence motif is a particular pattern in the sequence of amino acids or nucleotides.